REALIZE-K: Potassium binder increases MRA use in patients with hyperkalemia and HFrEF

Daily use of an oral potassium binder may allow the safe use of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure with reduced ejection fraction (HFrEF) who are at risk for hyperkalemia, results from the REALIZE-K trial show.

At 6 months, 71% of patients receiving sodium zirconium cyclosilicate (SZC) achieved the primary endpoint of normokalemia when receiving spironolactone ≥ 25 mg/day without treatment for hyperkalemia compared with 36% of patients receiving placebo (P <0.001). The study was presented Monday at the 2024 American Heart Association Scientific Sessions in Chicago, Illinois.

The REALIZE-K investigators, led by Michael Kosiborod, MD (St. Luke’s Mid-America Heart Institute, Kansas City, MO), say that both real and perceived risks of hyperkalemia are the primary reason for down-titration and discontinuation of MRAs in real life. patients with HFrEF in the world.

“Overall, there was no imbalance in adverse events or serious adverse events. The incidence of heart failure, edema and hyperkalemia was relatively small, but more participants experienced such events when taking CZK compared to placebo,” Kosiborod said in his presentation. “And in a post-hoc analysis, this difference appeared to be largely concentrated in patients with very high NT-proBNP levels at baseline.”

In recent DIAMOND A study of another potassium binder, patiromer (Veltassa; Vifor Pharma), also showed that it may improve the optimization of renin-angiotensin-aldosterone system inhibitors in patients with HFrEF. This study was stopped early due to COVID-19 and did not answer the question of how to use potassium binders to optimize individual therapy for HFrEF.

Panelist Larry A. Allen, MD (University of Colorado Anschutz Medical Campus, Aurora), said REALIZE-K “provides important data on the long-term and routine use of these drugs, allowing for guideline-compliant drug therapy.”

But he said potassium binders should be used with caution, mainly because of the significant sodium load they can produce in the body. This may be more of a problem for SZC than for patiromer.

“Each 5-gram packet of this drug contains 400 milligrams of sodium,” he noted. “And I think there is some concern that you are seeing higher levels of NT-proBNP as well as a trend toward increased hospitalizations for heart failure.”

Also important, Allen noted, is the issue of polypharmacy, since all other medications a patient receives must be taken 2 hours before or after the potassium binder.

IMPLEMENT-K Results

For the study, Kosiborod and colleagues enrolled patients from 85 centers in eight countries with symptomatic NYHA class II-IV HF and left ventricular ejection fraction <40%. Patients either had hyperkalemia at baseline (n = 95) or were at risk of developing it (n = 271) due to older age or chronic kidney disease. Kosiborod noted that at baseline the population was well optimized for HFpEF therapy other than MRA, with 99% of patients receiving an ACE inhibitor, ARB, or angiotensin-neprilysin receptor inhibitor.

During the open-label run-in period, all patients received spironolactone titrated to a target dose of 50 mg/day. Oral sodium SZC (10 g three times daily) was administered to patients with or at risk of hyperkalemia for up to 48 hours to normalize potassium levels and then tapered to a maintenance dose (10 g once daily). Patients with normal potassium levels (3.5–5.0 mEq/L) on sodium zirconium cyclosilicate and optimal doses of spironolactone (≥ 25 mg/day) were randomized to continue SZC or switch to placebo for 6 months.

In a sensitivity analysis of the primary endpoint that used a more conservative potassium threshold to define hyperkalemia, 84.8% of patients taking SZC achieved normokalemia when taking spironolactone ≥ 25 mg/day compared with 50.9% of patients taking placebo (P <0.001).

SZC was also more likely than placebo to improve four of five secondary endpoints: normokalemia with a randomized dose of spironolactone without treatment for hyperkalemia, normokalemia with spironolactone ≥ 25 mg/day, time to first episode of hyperkalemia, and time to first episode of hyperkalemia . reducing or discontinuing the dose of spironolactone due to hyperkalemia.

There were no differences between groups in quality of life assessed using the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score at 6 months.

Death or worsening HF occurred in 11% of patients in the SZC group compared with 3% in the placebo group (nominal log rank P = 0.034). There was one cardiovascular death in each group, while the incidence of heart failure was higher in the SZC group (10% versus 2% in the placebo group).

In a post hoc exploratory analysis, documented HF events occurred in seven of 24 patients in the SZC group compared with one of 16 in the placebo group, but among patients with NT-proBNP levels ≤ 4000 pg/mL, documented HF events occurred in three patients. 75 SZC participants compared to one in 80 placebo patients.

At 6 months, NT-proBNP levels were higher in the SZC group compared with placebo, but the difference did not reach statistical significance (P = 0.061). In addition, there was no difference between groups in the daily dose of loop diuretics.

A major concern for patients and physicians going forward is the cost of the potassium binder, Allen said.

“When it comes to insurance, coverage in the US varies: prior authorization is usually required, and copays can be significant. Without insurance, this drug costs $10,000 a year in the US,” he added.

Allen went on to say that it will be important to obtain data on patients who are truly at high risk for hyperkalemia and who need to add another drug to their regimen, versus those who can be controlled with diet and blood tests, to limit polypharmacy and additional costs. for medications.